Liposomes
The invention provides a diagnostic composition for administration to human or animal subjects, the composition containing multilamellar liposomes, optionally together with unilamellar liposomes, the liposomes containing at least one imaging agent and being suspended in an aqueous medium containing said imaging agent, wherein the liposomes comprise a neutral phospholipid and a charged phospholipid, the average particle diameter of the liposomes is 50-3000 nm and the concentration of imaging agent in any aqueous phase filling the interior of the liposomes is substantially the same as that in the aqueous medium in which the liposomes are suspended. The contrast agents concerned are typically X-ray, MRI or ultrasound contrast agents.
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Claims
1. An autoclaved diagnostic composition for administration to human or animal subjects, said composition containing multilamellar liposomes, optionally together with unilamellar liposomes, said liposomes containing an aqueous phase containing at least one X-ray or magnetic resonance imaging contrast agent, said liposomes being suspended in an aqueous medium containing said contrast agent, said liposomes comprising a neutral phospholipid and a charged phospholipid, the average particle diameter of said liposomes being 50-3000 nm, the concentration of said contrast agent in said aqueous phase being substantially the same as that in the aqueous medium in which said liposomes are suspended during the autoclaving process, and the concentration of total lipid in said composition being 50 mg/mL to 80 mg/mL.
2. A diagnostic composition according to claim 1 wherein the aqueous medium in which the liposomes are suspended is isotonic.
3. A diagnostic composition according to claim 1 or claim 2 wherein the neutral phospholipid and/or the charged phospholipid comprises at least one substantially saturated fatty acid residue containing at least 14 carbon atoms.
4. A diagnostic composition according to claim 1 wherein the neutral phospholipid and/or the charged phospholipid comprises at least one substantially saturated fatty acid residue containing up to 28 carbon atoms.
5. A diagnostic composition according to claim 1 wherein the neutral phospholipid is a phosphatidylcholine.
6. A diagnostic composition according to claim 1 wherein the charged phospholipid is a phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid or an ester of phosphatidic acid and an aminoalcohol.
7. A diagnostic composition according to claim 6 wherein the phosphatidyl group is a synthetic dipalmitoylphosphatidyl or distearoylphosphatidyl group.
8. A diagnostic composition according to claim 1 wherein the average particle diameter of the liposomes is 150 nm to 1000 nm.
9. A diagnostic composition according to claim 1 wherein the encapsulation capacity of the liposome is at least 5 ml/g.
10. A diagnostic composition according to claim 9 wherein the encapsulation capacity of the liposomes is at least 6 ml/g.
11. A diagnostic composition according to claim 1 wherein the weight ratio of the neutral phospholipid to the charged phospholipid is 60:1 to 4:1.
12. A diagnostic composition according to claim 1 wherein the concentration of total lipid is 20 mg/ml to 100 mg/ml.
13. A diagnostic composition according to claim 1 in which the X-ray contrast agent contains one or more iodinated phenyl groups or heavy metal clusters or chelates.
14. A diagnostic composition according to claim 13 wherein the contrast agent is iodixanol.
15. A diagnostic composition according to claim 1 wherein said contrast agent is a magnetic resonance imaging contrast agent.
16. A diagnostic composition according to claim 15 wherein said magnetic resonance imaging contrast agent contains manganese.
17. A diagnostic composition according to claim 15 wherein said magnetic resonance imaging contrast agent is a gadolinium chelate.
18. In a process for the production of an autoclaved diagnostic imaging contrast agent composition according to claim 1, wherein the improvement comprises dissolving a neutral phospholipid and a charged phospholipid in a solvent, removing the solvent to obtain a residue, mixing the residue with an aqueous solution containing an X-ray or magnetic resonance imaging contrast agent whereby liposomes are formed encapsulating said contrast agent, and autoclaving the mixture produced.
19. A process as claimed in claim 18 in which the liposomes so formed are extruded through a membrane filter to reduce their size.
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Type: Grant
Filed: Jun 6, 1995
Date of Patent: Oct 14, 1997
Assignees: Nycomed Imaging AS (Oslo), Daiichi Pharmaceutical Co., Ltd. (Tokyo)
Inventors: Jo Klaveness (Oslo), Arne Berg (Sandvika), Trond Vegard Jacobsen (Oslo), Pal Rongved (Nesoddtangen), Thorfinn Ege (Tranby), Hiroshi Kikuchi (Tokyo), Kiyoto Yachi (Tokyo)
Primary Examiner: Gollamudi S. Kishore
Law Firm: Bacon & Thomas
Application Number: 8/468,743
